To facilitate our studies of mouse eye mutants, we have been searching among inbred strains for genetic variation in lens crystallin genes using cDNA probes for Alpha -, Beta- and Gamma-crystallins. Southern blot analysis of Alpha-crystallin sequences has detected three restriction fragment size classes (Acry-1a,b,c) among 42 inbred strains of mice. The polymorphisms are due to insertions flanking the structural gene. Gene mapping experiments using 69 recombinant inbred strains demonstrated close linkage of Acry-1 to H-2K on chromosome 17. Estimated recombination distance is 1.4 cM. The Acry-1 -H-2 linkage was confirmed by analysis of 18 H-2 congenic and recombinant congenic strains, in which the presence of donor Acry-1 was completely concordant with the presence of donor H-2K. The Acry-1 - H-2 association has been maintained during the development of inbred strains and suggest that strong linkage disequilibrium may exist for these genes in natural populations. In only 1 of 42 strains tested was the H-2 haplotype not predictive of Acry-1 alleles. Conservation of genes in the MHC region of mice and humans implies that the human Alpha-crystallin gene is located on chromosome 6. Analysis of Beta-crystallin sequences (Bcry) by 17 endonucleases has failed to detect restriction polymorphisms in DNA from representative strains of mice. In contrast, Gamma-crystallin sequences (Gcry) have demonstrated restriction polymorphisms with all eight endonucleases so far employed. Genetic mapping experiments have been conducted on the Gamma-crystallin sequences using 48 recombinant inbred strains. We have found no recombination between Gcry and a Gamma-crystallin electrophoretic variant (LEN-1) previously mapped to chromosome 1 very close to the mutant gene, Elo, which produces anophthalmia in mice.